While a wide array of neuroprotective drugs substantially reduce infarct volume in animal stroke models, no neuroprotective agent has yet been shown to be beneficial for humans with stroke in definitive, phase III clinical trials. A crucial, quite possibly the crucial, factor that has hindered human clinical trials of neuroprotective drugs is delay in initiation of therapy. The long-term objective of this application's research project is to devise and validate methods to initiate neuroprotective therapy more quickly. The project's specific aim is to demonstrate that paramedic administration of a neuroprotective agent, magnesium sulfate, in the field to acute stroke patients can be performed practically and safely, and is more effective than delayed, in- hospital initiation of neuroprotective treatment. Three sequential clinical trials will be conducted. In each of these trials, paramedics will identify patients with acute stroke employing the Los Angeles Prehospital Stroke Screen, a prehospital stroke recognition instrument developed by the investigators. Study 1 will be an open-label, nonrandomized safety trial. Paramedics will administer magnesium sulfate to 20 stroke patients in the field over 18 months. Clinical outcome measures will be analyzed to demonstrate the safety, feasibility, and timesaving of prehospital therapy. Study 2 will then commence, a randomized, double-blind, placebo-controlled trial of magnesium in the field. Paramedics will initiate study agent, either magnesium or placebo, in the field to 30 patients over 24 months. This study will demonstrate the feasibility of performing randomized, controlled clinical trials of promising neuroprotective agents in the field. In the last 18 months of the grant, Study 3 will be performed, a pilot, randomized, double-blind, controlled trial of prehospital vs in-hospital initiation of magnesium/neuroprotective therapy. This study will explore the hypothesis that prehospital initiation of neuroprotective therapy is more efficacious than in-hospital initiation, and will provide data for the design of a larger, multicenter trial to definitively demonstrate the advantages of prehospital therapy. This award will also support Dr. Saver's work mentoring trainees in patient-oriented clinical research in cerebrovascular disease. This training program will help meet an urgent national need for clinical investigators in stroke created by projected dramatic increases in stroke occurrence in the American populace over the next five decades, and by dynamic recent basic science and clinical research advances in acute stroke therapy and stroke prevention.